The goal of our proposed research is to discover the anatomical failures that cause anterior compartment (AC) prolapse. AC prolapse is clinically manifest as the inter-related problems of cystocele and uterine prolapse. Emerging research suggests that AC prolapse involves four fascial failure sites: 1) apical descent, 2) transverse defects, 3) midline defects and 4) paravaginal defects. Muscle defects in the pubic portion of the levator ani (LAP) are also involved. In Years 06-09 we quantified the roles of factors 1, 2 and LAP defects and established their role in AC failure. A specific knowledge gap now concerns the role of factors 3 & 4 and how they combine with LAP to cause AC prolapse. The interactions between all 4 fascial failures and LAP defects in causing prolapse have also not been evaluated (AIMS 1 & 3). In years 06-09 we also discovered distortion in the structurally important paravaginal complex (PVC) that is associated with increased AC prolapse. The PVC includes the arcus tendineus fascia pelvis (ATFP), arcus tendineus levator ani (ATLA) and LAP. It is not known which of these structures are involved in the PVC distortion or why their structural failure increases prolapse (AIMS 2 & 3). In AIM 1 we will use novel techniques to create and measure MR-based models of AC anatomy at peak Valsalva to determine the relative contribution of factors 3 (midline defect) and 4 (paravaginal defect) to AC prolapse in 81 cases with anterior compartment prolapse and 72 matched normal controls. LAP cross sectional area (CSA) measures will be made using MR-based modeling techniques developed in the previous funding cycle. We will then establish the relative contributions of each of the 4 fascial failure sites and their interactions with LAP CSA. In AIM 2 we will identify the structural changes present in PVC distortion by making MR-based models of these structures in unique scans of 26 subjects with unilateral PVC distortion that allow the two fascial arches and LAP CSA in a distorted side to be compared with the same structures of a normal side in the same women. We will also make comparisons between 26 women with, and 26 women without bilateral distortion. In AIM 3 we will develop and refine the 3rd generation of our award-winning 3D finite element biomechanical model. We will test at least three hypotheses regarding the biomechanical consequences of the alterations found in AIMS 1 and 2 on the development of AC prolapse. We will then explore the propensity for prolapse progression based on a number of important biomechanical factors and their interactions. These results will provide critical insights needed to reduce operative failures by providing a more accurate understanding of the pathomechanics of AC prolapse. PUBLIC HEALTH RELEVANCE: Pelvic organ prolapse requires surgery in over 200,000 American women annually and anterior compartment prolapse is both the most common type of prolapse, and the most frequent site of recurrence. At present, the structural failures responsible for this problem are poorly understood and the reasons for frequent recurrence are unknown. This project seeks to use newly developed techniques of advanced imaging and biomechanical modeling to identify which structural failures are responsible for anterior compartment prolapse so that more specific treatment and prevention can be undertaken.